This invention relates to novel carboxylic acid esters having antifungal activity. More particularly it relates to novel sordaricin derivatives, to processes for their preparation, to pharmaceutical compositions containing them and to their use in medicine, more particularly in the prevention or treatment of diseases in animals, including humans, caused by fungal infection.
British Patent Specification No. 1,162,027 describes the preparation of an antibiotic, SL2266, by the cultivation of the strain NRRL 3196 of the fungus species Sordaria araneosa. SL 2266, later named sordarin, is reported to have fungistatic activity. The same research group also described in Helvetica Chimica Acta (1971), 51, 119-120 the degradation of sordarin to sordaricin. Published Japanese Patent Application No. J6 2040292A describes the preparation of an antibiotic, zofimarin, which is reported to have antifungal activity.
Sordarin, sordaricin and zofimarin may be represented by formula (A) below 
Although sordarin and zofimarin exhibit antifungal activity, both compounds are only moderately active and have limited spectra of action when tested against a battery of fungal organisms.
WO96/14326 and WO96/14327 describe novel sordarin derivatives which exhibit useful antifungal activity. WO99/09974 and WO99/09975 describe 4-cyano-4-deformyl sordarin and sordaricin derivatives which exhibit antingal activity.
We have now found a novel group of sordaricin derivatives which exhibit a useful spectrum of antifungal activity when administered orally and which can be conveniently prepared from readily available starting material.
Thus according to a first aspect of the invention, we provide compounds of formula (I); 
and physiologically acceptable salts wherein R1 represents C1-6 straight or branched chain alkyl, C1-6 straight or branched chain alkoxy, optionally substituted phenoxy. C3-6 straight or branched chain alkenyloxy (optionally substituted by 1 or 2 halogen atoms) or C1-4 straight or branched alkoxy substituted by an optionally substituted phenyl group, C3-8 straight or branched chain alkynyl, C3-6 straight or branched chain alkenyl (optionally substituted by C1-4 alkoxy or 1 or 2 halogen atoms), optionally substituted phenyl, optionally substituted C3-7 cycloalkyl, optionally substituted C5-7 cycloalkenyl, C2-4 straight or branched chain alkyl substituted by (C1-4 alkoxy, C1-4 alkyl thio or halogen), C1-4 straight or branched chain alkyl substituted by (C1-4 alkoxycarbonyl, arylalkyloxycarbonyl, aryloxycarbonyl, propadienyl, cyano, optionally substituted C3-7 cycloalkyl, optionally substituted 5 or 6 membered heteroaryl, or 1 or 2 optionally substituted phenyl groups), or methyl substituted by C1-6 alkanoyl or optionally substituted benzoyl; R2 represents a group selected from hydrogen, C1-6 straight or branched chain alkyl, C3-6 straight or branched chain alkenyl, optionally substituted phenyl or C1-4 alkyl substituted with a group selected from C1-4 alkoxy, hydroxy, acyloxy, alkoxycarbonyl or aryloxycarbonyl, and R3 represents a group selected from formyl or cyano; R represents phthalidyl, (2-oxo-5methyl-1,3-dioxolen-4-yl)methyl or the group CHR4 OCO(O)pR5 wherein R4 is hydrogen or C1-4 alkyl, p is zero or 1, R5 is C1-6 alkyl, C5-8 cycloalkyl (optionally substituted by C1-3 alkyl or carboxyl), C1-4 alkyl substituted by C1-3 alkoxy or carboxyl, C1-6 alkyl substituted by one or more groups selected from amino, (C1-4 alkylamino di(C1-4 alkyl)amino or carboxyl, phenyl (optionally substituted by carboxyl or aminoalkyl, C1-4 alkylaminoalkyl or di(C1-4 alkyl)aminoalkyl, or R5 is a 5-8 membered heterocyclic group containing 1 or 2 heteroatoms selected from oxygen or nitrogen.
Physiologically acceptable salts of the compounds of formula (I) include salts formed with physiologically acceptable acids, and where the compound contains a carboxyl group then the invention also includes salts with a physiologically acceptable base.
Suitable physiologically acceptable acid addition salts includes those formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid or sulphuric acid and organic acids such as acetic acid, propionic acid, succinic acid, lactic acid, tartaric acid, citric acid, maleic acid, benzoic acid or salicylic acid.
Suitable physioligically acceptable base addition salts include those formed with alkali and alkaline metal earths e.g. sodium or potassium salts, or with physiologically acceptable organic bases.
References hereinafter to a compound of formula (I) includes that compound and physiologically acceptable salts thereof.
Other salts which are not physiologically acceptable may be useful in the preparation of compounds of formula (I) and these form a further aspect of the invention.
It is to be understood that the present invention encompasses any individual isomers, including optical isomers and rotamers, of compounds represented by formula (I) above as well as mixtures thereof, including wholly or partially racemic mixtures thereof.
The term alkyl when used above to refer to a group or part of a group e.g. alkoxy includes straight or branched chain alkyl groups.
When R1 is C1-6 straight or branched chain alkyl group examples of such groups include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secondary butyl or tertiary butyl, pentyl, isopentyl, 1-ethylpropyl, hexyl or isohexyl.
When R1 is C1-4 straight or branched alkoxy substituted by optionally substituted phenyl examples of such groups include phenylmethoxy, phenylethoxy or phenylpropoxy.
When R1 is C1-6 straight or branched alkoxy examples of such groups include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, pentoxy or hexyloxy.
When R1 is a C3-6 alkenyl group examples of such groups include allyl, 2-methylallyl, 3-methylallyl or 3,3-dimethylallyl.
When R1 is a C3-6 alkenyl group substituted by C1-4 alkoxy this is conveniently C3-6 alkenyl substituted by methoxy e.g. 2-methoxyallyl or 2-methoxymethylallyl.
When R1 is C3-6 alkenyl substituted by one or two halogen atoms this is conveniently C3-6 alkenyl substituted by 1 or 2 halogen atoms selected from fluorine chlorine or bromine e.g. 2-fluoromethylallyl, 2-chloroallyl, 2-bromoallyl, 2-fluoroallyl, 3-fluoroallyl or 3,3-difluoroallyl.
When R1 is C3-6 alkenyloxy optionally substituted by 1 or 2 halogen atoms this is conveniently C3-6 alkenyloxy optionally substituted by bromine or chlorine or fluorine e.g. allyloxy, 2-chloroallyloxy, 2-bromoallyloxy, 2-fluoroallyloxy.
The term aryl as a group or part of a group means optionally substituted phenyl.
The term optionally substituted phenyl as a group or part of a group e.g. phenoxy or phenylalkyl includes phenyl or phenyl substituted by 1 or 2 groups which may be the same or different and selected from C1-4 alkyl, halogen (fluorine, chlorine, bromine or iodine), hydroxy, C1-4 alkoxy, methylenedioxy or trifluoromethyl.
The term optionally substituted C3-7 cydoalkyl as a group or part of a group is a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl group which may be substituted by 1 or 2 methyl, methoxy, hydroxy or phenyl groups or may be fused to a phenyl ring to form a bicyclic ring system linked to the rest of the molecule via a carbon atom in with the cyloalkyl ring e.g. indanyl or tetrahydronaphthyl.
When R1 is a C2-4 alkyl group substituted by halogen examples of suitable groups include 2-chloroethyl, 2-fluoroethyl, trifluoroethyl.
The term straight or branched C3-6 alkynyl includes 2-propynyl, 1-methyl-2-propynyl and 3-methyl-2-propynyl or 1,1-dimethyl-2-propynyl.
When R1 is C5-7 cycloalkenyl examples of such groups include cyclohexen-3-yl or cyclopenten-3-yl.
When R1 is C1-4 alkyl substituted by heteroaryl group, the term heteroaryl refers to a 5 or 6 membered heteroaryl group wherein the 5 membered group contains a single heteroatom selected from oxygen, sulphur or nitrogen and optionally contains 1 or 2 further nitrogen atoms, and the 6 membered group contains from 1 to 3 nitrogen atoms. Examples of such heteroaryl groups include furanyl, thienyl, pyrrolyl, oxazolyl, iso-oxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, pyridyl, pyrimidiyl, pyridazinyl, pyrazinyl or triazinyl. The said heteroaryl groups may be substituted by one or two groups selected from C1-4 alkyl e.g. methyl, hydroxyalkyl e.g. hydroxymethyl, acyloxyalkyl e.g. acetoxymethyl or halogen.
When R2 is C1-6 alkyl examples of such groups include methyl, ethyl, propyl, butyl, t-butyl.
When R4 is C1-4 alkyl examples of such groups include methyl, ethyl or propyl.
When R5 is C1-6 alkyl examples of such groups indude, methyl, ethyl or t-butyl.
When R5 is C5-8 cyloalkyl optionally subsitutued by C1-3 alkyl or carboxy examples of such groups include cyclohexyl optionally substituted by C1-2 alkyl e.g. 4-ethylcyclohexyl, or cyclohexyl subsitutued by carboxy at the 3 or 4 positions.
When R5 is C1-4 alkyl substituted by C1-3 alkoxy examples of such a group include methoxymethyl or methoxyethyl. When R5 is C1-6 alkyl substituted by one or more amino, C1-4 alkylamino, di(C1-4 alkyl)amino or carboxy groups examples of such groups include 2-amino-3-methylbutyl, 2-dimethylamino-3-methybutyl, 2-carboxyethyl, 3-carboxy-ethyl or 2-amino-3 carboxyethyl.
When R5 is phenyl (optionally substituted carboxyl, aminoalkyl, C1-4 alkylaminoalkyl or di(C1-4 alkyl)aminoalkyl examples of such groups include phenyl 4-carboxyphenyl, or 4-dimethylaminomethylphenyl.
When R5 is a 5-8 membered heterocyclic group containing one or two heteroatoms selected from oxygen or nitrogen. Examples of such groups include piperidin-4-yl or tetrahydropyran-2-yl.
Examples of suitable R1 groups include C1-6 alkyl (such as methyl, ethyl, propyl, isopropyl, n-butyl, 1-methylpropyl, t-butyl, 1-ethylpropyl, pentyl, 3-methylbutyl, 3,3-dimethylbutyl), C1-4 alkoxy e.g. methoxy, C1-4 alkoxy substituted by phenyl (e.g. phenylmethoxy), phenoxy, C2-4 alkyl substituted by C1-4 alkoxy (e.g. methoxyethyl, ethoxyethyl, ethoxypropyl, isopropoxypropyl), C2-4 alkyl substituted by C1-2 alkylthio (e.g. ethylthioethyl), C2-4 alkyl substituted by halogen (e.g. 2-chloroethyl, 2,2,2 trifluroethyl), C1-4 alkyl substituted by cyano (e.g. cyanomethyl or cyanoethyl), C1-4 alkyl substituted by propadienyl (e.g. 2,3-butadienyl) optionally substituted C3-6 cycloalkyl e.g.[ (cyclopropyl optionally substituted by phenyl), cyclobutyl, cyclopentyl, cyclohexyl (optionally substituted by hydroxy or alkyl e.g. methyl), indanyl or tetrahydronaphthyl], phenyl, C1-4 alkyl substituted by optionally substituted furanyl (e.g. furanylmethyl, hydroxymethylfuranylmethyl, acetoxymethylfuranylmethyl), pyridyl (e.g. pyridylmethyl or pyridylethyl), optionally substituted pyrrole e.g. (1-methylpyrrolemethyl) optionally substituted thiazolyl e.g. (thiazolylmethyl) optionally substituted imidazole e.g. N-hydroxymethylimidazolylmethyl, C1-4 alkyl substituted by C1-2 alkoxycarbonyl (e.g. methoxycarbonylethyl, 1-methoxycarbonyl-2-methylpropyl), aralkyloxycarbonyl (e.g. benzyloxycarbonylmethyl) or aryloxycarbonyl (e.g. phenoxy carbonylmethyl), C1-4 alkyl substituted by optionally substituted C3-8 cycloalkyl (e.g. cyclopropylmethyl, cyclohexylmethyl, cyclohexylethyl, 1-yclohexylethyl), C3-6 alkenyl (e.g. allyl, 2-methylallyl, 3-methylallyl, 3,3-dimethylallyl), C3-8 alkenyl substituted by alkoxy e.g. 2-methoxyallyl, 2-methoxymethylallyl, C3-6 alkenyl substituted by 1 or 2 halogen atoms selected from chlorine, bromine or fluorine e.g. (2-fluoromethylallyl, 2-chloroallyl, 2-bromoallyl, 2-fluoroallyl, 3-fluoroallyl, 3,3-difluoroallyl), C3-6 alkenyloxy optionally substituted by halogen (e.g. allyloxy, 2-chloroallyloxy), C1-4 alkyl substituted by 1 or 2 optionally substituted phenyl groups [wherein the optional substituent in the phenyl ring is selected from 1 or 2 halogen atoms, e.g. chlorine or fluorine, trifluromethyl, hydroxy, methoxy or methylenedioxy; (examples of such groups include optionally substituted benzyl e.g. benzyl, 4-methoxybenzyl, 4-trifluromethylbenzyl, difluorobenzyl such as 2,6-diflurobenzyl, 3,4-diflurobenzyl, 2,5-difluorobenzyl, or 2,4-difluorobenzyl, methylenedioxybenzyl, 1-phenyl ethyl, phenethyl (optionally substituted by 1 or 2 hydroxyl groups, methoxy, halogen e.g. fluorine or chlorine), phenylpropyl or diphenylmethyl)], C3-8 alkynyl e.g. 2-propynyl, 1-methyl-2-propynyl, 3-methyl-2-propynyl, C5-7 cycloalkenyl e.g. 1-cyclohexen-3-yl, or methyl substituted by acetyl or benzoyl.
Examples of suitable R2 groups include methyl, ethyl, t-butyl and phenyl.
Conveniently R is a group selected from phthalidyl, (2-oxo-5-methyl-1,3-dioxolen-4-yl) methyl or the group HC(R4) OCO(O)pR5 wherein R4 is hydrogen or methyl and R5 is ethyl, t-butyl, 2-amino-3-methyl butyl, 2-carboxy-2-aminoethyl, 4-carboxyphenyl or 4-dimethylaminomethyl and more preferably p is zero.
Conveniently R1 is a group selected from C1-6 alkyl e.g. methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, t-butyl, n-pentyl, 3-methylbutyl, C1-4 alkoxy e.g. methoxy, C3-6 alkenyloxy (optionally substituted by halogen e.g. allyloxy, 2-chloroallyloxy), optionally substituted phenyl e.g. phenyl, C3-6 cycloalkyl e.g cyclopropyl, cyclobutyl, cyclopentyl, indanyl, tetrahydronaphthyl, C2-4 alkyl substituted by C1-2 alkoxy, e.g. methoxyethyl or ethoxypropyl, C2-4 alkyl substituted C1-2 alkylthio e.g. ethylthioethyl, C1-4 alkyl substituted by cyano e.g. cyanoethyl or cyanomethyl, C1-4 alkyl substituted by propadienyl e.g. 2,3-butadienyl, C1-4 alkyl substituted by alkoxycarbonyl (e.g. methoxycarbonylmethyl), C1-4 alkyl substituted by C3-7 cycloalkyl e.g. cyclopropylmethyl, C1-4 alkyl substituted by heteroaryl e.g. furylmethyl, pyridylmethyl, N-methylpyrrolylmethyl or thiazolylmethyl, C1-4 alkyl substituted by 1 or 2 optionally substituted phenyl groups e.g phenylmethyl, diphenylmethyl, difluorophenylmethyl (wherein the two fluorine atoms are in the 2,6, 2,4, 3,4 or 3,5 positions), trifluromethylphenylmethyl, methylenedioxyphenylmethyl, methoxyphenylmethyl, 1-phenylethyl or phenylethyl, C3-6 alkenyl e.g allyl, 2-methylallyl, 3-methylallyl, 3,3-dimethylallyl, C3-6 alkynyl e.g. 2-propynyl, C3-6 alkenyl substituted by C1-4 alkoxy e.g. 2-methoxyallyl, 2-methoxymethylallyl, C3-6 alkenyl substituted 1 or 2 halogen atoms selected from chlorine, bromine or fluorine e.g. 2-chloroallyl, 2-bromoallyl, 2-fluoromethylallyl, 2-fluoroallyl, 3-fluoroallyl, 3,3-difluoroallyl, C5-7 cycloalkenyl e.g cyclohexen-3-yl or methyl substituted by acetyl or benzoyl.
Preferred R1 groups include, methyl, ethyl, propyl, isopropyl, butyl, 1-methylpropyl, 3-methylbutyl, methoxy, cyclopropyl, allyl, 2-methylallyl, allyl substituted by halogen e.g. 2-chloroallyl, 2-fluoromethylallyl, 2-bromoallyl, 3,3-difluoroallyl, phenyl, ethylthioethyl, methoxyethyl, benzyl, furylmethyl, 2,6-difluorophenylmethyl, 3,4-difluorophenylmethyl, 3,5-difluorophenylmethyl, 3,4-methylenedioxyphenylmethyl, 4-methoxyphenylmethyl, 1-phenylethyl or propynyl, 2,3-butadienyl, allyloxy, 2-chloroallyloxy.
Preferred R2 groups include methyl, ethyl, t-butyl or phenyl and more particularly methyl.
A preferred R3 group is CHO.
A preferred group of compounds of formula (I) are those wherein R2 is methyl and more particularly where R3 is also CHO.
Preferred R groups include phthalidyl or CH(R4)OCO(O)pR5 wherein R4 is hydrogen or methyl and R5, ethyl or t-butyl and p is zero or 1.
Compounds according to the inventions when administered orally exhibit a high level of antifungal activity against a wide range of pathogenic micro-organisms. Thus the compounds of formula (I) are useful in combating fungal and or protozoal infections in animals, including humans. For example, they may be used in the treatment of fungal infections including those caused by one or more organisms such as species of Candida (e.g. Candida albicans, Candida glabrata, (Torulopsis glabrata), Candida tropicalis, Candida parapsilosis and Candida pseudotropicalis), Cryptococcus neoformans, Aspergillus Spp (e.g. Aspergillus flavus and Aspergillus fumigatus), Coccidioides (e.g. Coccidioides immitis), Paracoccidioides (e.g. Paracoccidioides brasiliensis), Histoplasma (e.g. Histoplasma capsulatum) or Blastomyces (e.g. Blastomyces dermatitidis). They may also be used to treat other fungal infections caused by species of Trchophyton, Microsporum or Epidermophyton (e.g. Trichophyton mentagrophytes, Trichophyton rubrum, Microsporum canis or Epidermophyton floccosum), or in mucosal infections caused by Candida albicans. 
Compounds of formula (I) may also be used to treat other infections caused by other fungi such as Geotrichum (e.g. Geotrichum clavatum), Trichosporon (e.g. Trichosporon beigelii), Blastoschizomyces (e.g. Blastoschizomyces capitatus), Sporothrix (e.g. Sporothrix schenckii), Scedosporium (e.g. Scedosporium apiosperum), Cladosporium (e.g. Cladosporium carrionii) and Pityrosporum ovale. 
The compounds of formula (I) may also be used to treat infections caused by protozoa such as Toxoplasma, Cryptosporidium, Leishmania, Tripanosoma, Giardia and Trichomonas.
The compounds of formula (I) may also be used to treat infections caused by Pneumocystis Carinii. 
The antifungal activity of the compounds of formula (I) may be determined using conventional in vitro and in vivo screens.
The in vitro evaluation of the anti-fungal activity of compounds of the invention was performed on liquid or solid medium by the anti-fungal two-fold serial dilution technique of determining the minimum inhibitory concentration (MIC) of anti-fungal agent that inhibited development of growth after 24 to 48 hours of incubation at 37xc2x0 C. For example a series of agar plates or broth microdilution panels containing two-fold dilutions of anti-fungal agent were inoculated with a standard culture of a clinically relevant pathogen, in the presence and absence of activated or inactivated serum. The agar plates or broth microdilution panels were then examined for the presence or absence of growth of the fungus and the appropriate MIC values determined. The compounds of the invention show little or no activity when the test is carried out in the absence of activated or inactivated serum, but exhibit significant activity when the test is carried out in the presence of the serum.
The fungicidal activity of the compounds of formula (I) may also be determined in conventional in vivo tests in animals e.g. rats and mice, such as the lethal systems candidiasis test in mice.
Compounds of the invention show particularly useful activity against one or more of the organisms selected from Candida albicans, Candida glabrata, Candida tropicalis, Candida parapsilosis, Pneumocystis carini Coccidioides immitis, Paracoccidioides brasiliensis, Histoplasma capsulatum and Blastomyces dermatitides. 
In view of their antifungal and or antiprotozoal activity, compounds of formula (I) recommend themselves for the treatment of a variety of fungal and or protozoal infections in human beings and animals. Such infections include superficial, cutaneous, subcutaneous and systemic mycotic infections such as respiratory tract infections, gastrointestinal tract infections, cardiovascular infections, urinary tract infections, CNS infections, candidiasis and chronic mucocandidiasis (e.g. thrush and vaginal candidiasis) and skin infections caused by fungi, cutaneous and mucocutaneous candidiasis, dermatophytoses induding ringworm and tinea infections, athletes foot, paronychia, pityriasis versicolor, erythrasma, intertrigo, fungal nappy rash, candida vulvitis, candida balanitis and otitis extema. They may also be used as prophylactic agents to prevent systemic and topical fungal infections. Use as prophylactic agents may, for example, be appropriate as part of a selective gut decontamination regimen in the prevention of infection in immunocompromised patients (e.g. AIDS patients, patients receiving cancer therapy or transplant patients). Prevention of fungal overgrowth during antibiotic treatment may also be desirable in some disease syndromes or iatrogenic states. They may also be used in the prophylaxis and or treatmentof infections caused by Pneumocystis carinii. 
Thus in a further aspect the invention provides a method of the treatment of human or non human animal body to prevent or treat fungal and or protozoal diseases, which method comprises administering to solid body an effective amount of a compound of formula (I).
The invention also provides for the use of a compound of formula (I) in the manufacture of a medicament for the treatment or prevention of fungal and or protozoal infections.
While it is possible that, for use in therapy, compounds of the invention may be administered as the raw chemical, it is preferable to present the active ingredient as a pharmaceutical formulation. The invention thus further provides a pharmaceutical formulation comprising compounds of formula (I) and physiologically acceptable salts thereof together with one or more pharmaceutically acceptable carriers thereof and, optionally, other therapeutic and/or prophylactic ingredients. The carrier(s) must be xe2x80x98acceptablexe2x80x99 in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The compositions of the invention include those in a form especially formulated for oral, buccal, implant, rectal, topical, ophthalmic or genito-urinary administration or in a form suitable for administration by inhalation or insulffation.
Tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, mucilage of starch or polyvinylpyrrolidone; fillers, for example, lactose, sugar, microcrystalline cellulose, maize-starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch or sodium starch glycollate or crosscarmellose sodium; wetting agents such as sodium lauryl sulphate and pH modifiers for example citric acid, malic acid, tartaric acid, sodium carbonate, sodium bicarbonate, triethanolamine or trometamol. The capsule may contain powders, tablets, pellets, granules, liquids, waxes, surfactants or any combination of the former, which may be coated according to the methods well known to the art. The content of the capsules can be made of: binding agents, fillers, lubricants, desintegrants, wetting agents and pH modifiers, as described above. The tablets which include chewable, dispersible or effervescent tablets may be coated according to methods well known in the art.
Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methyl cellulose, glucose/sugar syrup, gelatin, hydroxyethylcellulose, carboxymethyl cellulose, aluminium stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan mono-oleate or acacia; non-aqueous vehicles (which may include edible oils), for example, almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; and preservatives, for example, methyl or propyl p-hydroxybenzoates or sorbic acid and flavouring agent.
For buccal administration the composition may take the form of tablets or lozenges formulated in conventional manner.
For administration by inhalation the compositions according to the invention are conveniently delivered in the form of an aerosol spray presentation from pressurised packs with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas, or from a nebuliser. In the case of a pressurised aerosol the dosage unit may be determined by providing a valve to deliver a metered amount.
Alternatively, for administration by inhalation the compositions according to the invention may take the form of a dry powder composition, for example a powder mix of the compound and a suitable powder base such as lactose or starch or as a modified physical form of the drug substance alone. The powder composition may be presented in unit dosage form in, for example, capsules or cartridges of e.g. gelatin, or blister packs from which the powder may be administered with the aid of an inhaler or insulator.
The compositions may take the form of a suppository, e.g. containing a conventional suppository base, or a pessary, e.g. containing a conventional pessary base.
The compositions may also be formulated for topical administration in the form of ointments, creams, gels, lotions, shampoos, powders (including spray powders), pessaries, tampons, sprays, dips, aerosols, drops (e.g. eye, ear or nose drops) or pour-ons. Ointments and creams may, for example, be formulated with an aqueous or oily base with the addition of suitable thickening and/or gelling agents. Ointments for administration to the eye may be manufactured in a sterile manner using sterilised components. Pour-ons may, for example, be formulated for veterinary use in oils containing organic solvents, optionally with formulatory agents, e.g. stabilising and solubilising agents. Pessaries and tampons for vaginal insertion may be formulated using conventional techniques and, where appropriate, may contain an effervescent vehicle. Such compositions may also contain other active ingredients such as corticosteroids, antibiotics or antiparasitics as appropriate.
Liquid preparations for intranasal delivery may take the form of solutions or suspensions and may contain conventional excipients such as tonicity adjusting agents, for example, sodium chloride, dextrose or mannitol; preservatives, for example benzalkonium chloride, thiomersal, phenylethyl alcohol; and other formulating agents such as suspending, buffering, stabilising, dispersing and or flavouring agents.
Transdermal administration may be affected by the design of a suitable system which promotes absorption of the active compound through the skin and would typically consist of a base formulation enclosed within an adhesive stick-on patch comprising backing films, membranes and release liners. Such systems may include absorption enhancers such as alcohols or work by promoting ionotophoresis.
The composition according to the invention may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection. Thus, for example, a compound of the invention may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
When the compositions comprise dosage units, each unit will preferably contain 0.001 mg to 1000 mg, advantageously 0.01 mg to 400 mg, of active ingredient where a compound of the invention is to be administered orally. The daily dosage as employed for adult human treatment will preferably range from 0.001 mg to 5000 mg of active ingredient, most preferably from 0.01 mg to 2000 mg which may be administered in 1 to 4 daily doses, for example, depending on the route of administration and on the condition of the patient and the disease to be treated.
The compound may be administered by intravenous infusion using, for example, up to 50 mg/kg/day of the active ingredient. The duration of treatment will be dictated by the rate of response rather than by arbitrary numbers of days.
Compounds of the invention may also be used in combination with other therapeutic agents, and the invention thus provides, in a further aspect, a combination comprising a compound of the invention together with another therapeutically active agent.
Thus for example the compounds of the invention may be used in combination with one or more other antifungal agents, such as a polyenic derivative e.g. (Amphotericin B, Nystatin, a lipid formulation of Amphotericin B) an azole derivative e.g. (Fluconazole, Intraconazole, Ketoconazole, Miconazole, Clotrimazole, ZD-08070, UK-109496), 5-Fluorocytosine, a Pneumocandin or Echinocandin derivative (such as Cilofungin, LY-303366, L-733560), an allylamine derivative (e.g. Terbinafine, Butenafine or Naftifine), and/or one or more immunomodulating agents such as an interferon e.g. (IFN-xcex3), interleukine e.g. (IL-1, IL-2, IL-3 and IL-8) and colony stimulating factors, [(G)-CSF, (M)-CSF and (GM)-CSF] and defensines. Particularly advantageous compounds for use with compounds of the invention include Intraconazole, Flucytosine, Fluconazole, Terbinafine or Amphotericin B.
When the compounds of the invention are administered in combination with another antifungal agent the compounds of the invention and the other fungal agent can be administered at the recommended maximum clinical dosage or at lower doses.
The combinations referred to above may conveniently be presented for use in the form of a pharmaceutical formulation and thus pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier thereof comprise a further aspect of the invention. The individual components of such combinations may be administered either sequentially or simultaneously in separate or combined pharmaceutical formulations.
When a compound of the invention is used in combination with a second therapeutic agent against the same condition the dose of each compound may differ from that when the compound is used alone. Appropriate doses will be readily appreciated by those skilled in the art.
According to another aspect of the present invention, we provide a compound of formula (I) or a physiologically acceptable salt thereof or a pharmaceutical composition comprising a compound of formula (I) or a physiologically acceptable salt thereof as defined above for use in therapy, particularly for the treatment of fungal infections in animals (especially humans).
According to another aspect of the present invention, we provide the use of a compound of formula (I) or a physiologically acceptable salt thereof in the manufacture of a medicament for the treatment of fungal infections in a human or non-human animal patient.
According to a further aspect of the present invention, we provide a method of treatment of the human or non-human animal body to combat fungal diseases, which method comprises administering to said body an effective amount of a compound of formula (I) or a physiologically acceptable salt thereof.
It will be appreciated by those skilled in the art that references herein to treatment extend to prophylaxis as well as the treatment of established conditions or infections.
The invention also provides processes for the preparation of compounds of formula (I).
The compounds of formula (I) may be readily prepared by esterification of the corresponding carboxylic acid (II) or an alkali metal salt thereof wherein R1, R2 and R3 have the meaning defined in formula (I). 
by reaction with the compound R Y wherein R has the meanings defined in formula (I) or is a group convertible thereto and Y is a leaving group e.g. a halide. Conveniently the reaction is carried out in a polar solvent such as an ester e.g. ethyl acetate and or di-methylformamide, dimethylacetamide or N-methyl pyrrolidinone in the presence of a base e.g. an inorganic base such as sodium carbonate or bicarbonate and in the presence of a quatemary ammonium salt such as a tetrabutyl ammonium halide e.g. bromide or iodide.
The compounds of formula (II) may be prepared by the processes described and/or exemplified in WO99/58512 and which is incorporated herein by reference.
Compounds of formula (I) wherein R is the group CHR4OCO(O)pR5 and R4 is hydrogen may be prepared by reaction of the halomethyl ester (III), wherein R1, R2 have the meaning given on formula II and R3 is formyl or a protected formyl group, 
with the acid (IV; HOCO(O)pR5 wherein R5 has the meaning given in formula (I) or is a protected derivative thereof) or an alkali metal salt thereof in a solvent such as an aprotic solvent e.g. an aromatic hydrocarbon e.g. toluene or an ether e.g. tetrahydrofuran or mixtures thereof, followed by removal of any protecting groups.
The chloromethyl ester (III) may be prepared by treating the corresponding carboxylic acid of formula (II), with the chloromethyl derivative (V; ClCH2SO3 Cl) in the presence of a base such as sodium bicarbonate and in a solvent such as a halohydrocarbon e.g. dichloromethane or an aqueous mixture thereof.
Acid addition salts of compounds of formula (I) may be prepared by treating a solution of compound of formula (I) in a suitable solvent e.g. an ether such as diethyl ether or diisopropyl ether or an alkanol e.g. ethanol with an aqueous solution of the appropriate acid e.g. hydrochloric acid. The desired salt may then be isolated using conventional procedures.